Brain is the most significant region of central nerve system for information transmission via nerves such as motion and perception, and plays an important role in human mental activity such as feelings, emotions, reasoning or the like. Higher brain dysfunctions caused by cerebral trauma, cerebrovascular disorders, cerebritis, hypoxia or the like include a wide range of defects in memory, attention, executive functioning, social behavior and the like, and their characteristics vary depending on the part of the brain damage. Further, it is also reported that decline in brain function can be caused by fatigue (Non-Patent Literature 1), leading to decline in abilities such as memory learning, attention concentration, judgment or the like.
Citrulline is one of amino acids present as free form and is not used as a constituent for protein synthesis in vivo. In the body, citrulline serves as a precursor of arginine in arginine biosynthesis or an important component of NO cycle involved in nitric oxide (NO) supply. Ingested citrulline is mostly converted to arginine in the kidney and produced arginine is efficiently supplied systemically (Non-Patent Literature 2).
Arginine is an amino acid to be a direct substrate of nitric oxide (NO) synthase. Moreover, arginine is an intermediate in the urea cycle in the liver, and plays an important role in detoxication of ammonia produced in the body. NO synthesized from arginine as a substrate exerts a variety of physiological functions for maintaining normal vascular functions, including vasodilatation, inhibition of LDL oxidation, inhibition of platelet aggregation, anti-proliferation effect on smooth muscle cells, antioxidant effect and the like.
It is reported that ingestion of citrulline shows an anti-arteriosclerosis action and improves blood circulation via the production of the vasodilator NO (Non-Patent Literature 3), and citrulline is widely used around US as a food material for producing NO to improve blood circulation. Citrulline is also used in Europe as an anti-fatigue drug in the form of citrulline-malate.
Glutathione is a tripeptide composed of glutamic acid, cysteine, and glycine, and plays a central role in removing reactive oxygen species in vivo. Glutathione is also involved in the detoxification mechanism for removing xenobiotics from the body.
It is reported that ingestion of glutathione shows a hepatoprotective effect (Non-Patent Literature 4), a whitening effect (Non-Patent Literature 5), or the like. Owing to these functions, glutathione is used as a detoxifying agent when poisoned, as a drug for improving liver function, or as an antioxidant food material.
It is known that ischemic cerebrovascular disease causes brain neuronal cell death, leading to decline in brain function. The cause includes neurovascular damage, endothelial dysfunction, diminished cerebral blood flow or the like (Non-Patent Literature 6), and it is understood that a reduction of normal NO production in endothelial cells and diminished cerebral blood flow cause brain neuronal cell death and decline in brain function. In other words, it is expected that brain neuronal cells can be protected and decline in brain function can be prevented or improved by enhancing NO production in endothelial cells and cerebral blood flow.
Until now, there have been reports about improvement of attention concentration by oral ingestion of citrulline (Patent Literature 1) and improvement of memory learning ability by intraperitoneal injection of arginine (Non-Patent Literature 7). Further, it is reported that glutathione is involved in maintaining homeostasis of brain function (Non-Patent Literature 8), and decrease of brain tissue metabolism can be protected by glutathione infusion (Non-Patent Literature 9). However, there have been no reports that oral ingestion of glutathione shows the effect of preventing or improving decline in brain function, and a synergistic effect of preventing or improving decline in brain function can be obtained by using citrulline or a salt thereof in combination with glutathione or a salt thereof.